CLINICAL PHARMACOKINETICS THERAPEUTIC DRUG MONITORING

Rebecca E. Wrishko, Ph.D. Senior Pharmacokineticist

MARCH 25, 2004

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Learning Objectives
Define Clinical Pharmacokinetics Recognize the Differences between Wide and Narrow Therapeutic Windows Understand the Rational of Therapeutic Drug Monitoring Complete Clinical Case Examples Using Common Pharmacokinetic Equations Vancomycin Pharmacokinetics Gentamicin Pharmacokinetics

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Clinical Pharmacokinetics
Application of pharmacokinetic principles to the therapeutic management of patients in clinical pharmacokinetics. The magnitudes of both the desired response and toxicity are functions of the drug concentration at the site(s) of action.

The magnitudes of both the desired response and toxicity may be functions of the drug concentration at the site(s) of action.

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THERAPEUTIC WINDOW
Therapeutic failure results when either the concentration is too low, ineffective therapy, or is too high, producing unacceptable toxicity. Between these limits of concentration lies a region associated with therapeutic success regarded as a THERAPEUTIC WINDOW
This figure illustrates the concentrations that follow the administration of two regimens, A and B; whereby, the dosing interval is the same, but the dose given in B is TWICE that given in A.

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Therapeutic Window
Both the width of the therapeutic window and the rate of drug elimination govern the size of the maintenance dose and the frequency of administration. When the window is narrow and the drug is eliminated rapidly, small doses must be given often to achieve therapeutic success. In contrast, some drugs are administered relatively infrequently, producing large fluctuations in the plasma concentrations. The reasons may include: development of tolerance or need to produce high concentrations for short periods of time (antibiotics). For the majority of patients, knowledge of a drugs therapeutic plasma concentration range and pharmacokinetics should lead to a more rapid establishment of a safe and efficacious dosage regimen. The narrower the therapeutic range (factor of 2 3 difference between upper and lower limit), the more difficult to maintain values in it. Also, some drugs are used to treat several disease, and the therapeutic plasma concentration range may differ with the disease.
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Wide Therapeutic Window

WIDE THERAPEUTIC WINDOW
TOXICITY

EFFICACY

Here toxicity occurs at concentrations well above those needed to achieve maximum desired effect.

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Narrow Therapeutic Window

TOXICITY

NARROW THERAPEUTIC WINDOW

EFFICACY

The response curves overlap well below maximal efficacy, so it is difficult to find plasma concentrations that produce efficacy without some degree of toxicity.

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Therapeutic Drug Monitoring

Plasma concentration of a drug must correlate quantitatively with both the intensity and probability of therapeutic or toxic effects. A direct relationship between concentration and effect may be insufficient grounds for plasma concentration monitoring if the therapeutic effect itself is easily monitored. Most relevant when the objective is to maintain a therapeutic effect by maintaining a concentrations within a limited range and when the likelihood of toxicity can be predicted from the concentration. Important with narrow therapeutic window when therapeutic failure is likely. Dose adjustment can often be anticipated based upon the patients age, weight, and clinical status, especially renal, hepatic, and cardiovascular functions. Even after accounting for these factors, sufficient uncertainty often remains in the patient-specific (individual) kinetics of the drug to warrant plasma concentration monitoring.
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Therapeutic Drug Monitoring

Information required to evaluate measured plasma concentrations include:
History of Drug Administration Time of Sampling Present and Previous (if applicable) Plasma Drug Concentrations Clinical Status of the Patient Physiological Data Concurrent Drug Therapy

From such observations, the patients current pharmacokinetic parameters can be estimated, and a new dosage regimen can be designed to more closely achieve the target value(s).
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First Order Elimination

Elimination Rate Constant (ke) Characterizes the elimination process and is a true constant that is independent of concentration. Represents the fraction or % of the total amount of drug in the body removed per unit time. This behavior may be expressed as:

Function of clearance (elimination) and volume of distribution (amount of drug in the body).

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Elimination Rate Constant (ke)

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Half-life (t1/2)
More common to refer to the t1/2 rather than to the elimination rate constant of a drug. The t1/2 of a drug that is eliminated by first-order kinetics is concentrationindependent. Represents the amount of time required for the total amount of drug to decrease by 50% and may be expressed as:

Reflects rather than controls volume of distribution and clearance, two independent parameters.
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Half-life (t1/2)
Over 95% of the drug is lost or eliminated in 5 half-lives, which is typically considered to be the completion of the process.

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Clearance (CL)
Only represents the theoretical volume of blood or plasma that is completely cleared of drug in a given period of time. Total clearance is a proportionality factor relating drug elimination to the plasma concentration.

Note, rate of elimination decreases with time due to a decrease in drug concentration; however, the ability of the organs to remove the drug remains constant.

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Volume of Distribution (Vd)

Apparent Vd does not necessarily refer to a physiological volume, it is a mathematical factor relating the amount of drug in the body and the concentration of drug measured in the plasma.

Apparent Vd that is greater than the plasma compartment (3 L) only indicates that the drug is also present outside that compartment.

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Vancomycin
Therapeutic Indications
Infections caused by Methicillin-Resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). important pathogens in patients with prosthetic devices. Enterococcal and nonenterococcal infections in patients with a penicillin hypersensitivity. Sepsis caused by nondiptheria Corynebacterium species in the immunocompromised host. Pseudomembranous colitis (PMC) or antibiotic-associated Clostridium difficile colitis, mediated by the Clostridium difficile toxin. Prophylaxis against postoperative infections caused by gram positive organisms.

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Vancomycin Toxicity and Adverse Effects

Ototoxicity
Characterized by damage to the auditory nerve, leading to permanent hearing loss. Loss of accuity to high frequency tone and tinnitus are frequent antecedents. Generally considered that serum concentrations in the range of 80-100 mg/L are associated with auditory toxicity. Unclear whether excess peak or trough concentrations are primarily related to the development of ototoxicity.

Nephrotoxicity
Evidence suggests that the risk increases with increasing serum concentrations; however, a well-defined correlation has not been established. Unclear whether nephrotoxicity is due to underlying pathology, concurrent therapy with other nephrotoxic agents, or to the antibiotic.

Other Neutropenia and thrombocytopenia

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Vancomycin Therapeutic Drug Monitoring Desired peak serum concentrations = 30 - 40 mg/L Desired trough serum concentrations = 5 - 10 mg/L ! Due to large interpatient variability in the pharmacokinetics and potential ototoxicity and nephrotoxicity, serum concentrations should be monitored, especially in high-risk patients, those with renal impairment or who are given other ototoxic and/or nephrotoxic agents concurrently.

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Vancomycin Therapeutic Drug Monitoring

Monitoring serum concentrations has been a challenge to clinicians due to the distributional characteristics of the drug. ASSUMPTION: FIRST-ORDER ELIMINATION FROM ONE-COMPARTMENT.

The timing of serum sampling for peak concentrations has long been an area of controversy since times reported in the literature are inconsistent and do not permit an evaluation to discriminate ototoxicity associated with elevated distributive or elimination phase concentrations. A clinically rational time for drawing the peak concentration is 1 hour following the 1-hour intermittent intravenous infusion of the third dose. Often, a peak concentration may be obtained 3 hours following a 1hour intermittent intravenous infusion. ASSUMPTION: DISTRIBUTION IS COMPLETE WITH THIS SAMPLING STRATEGY.
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Vancomycin Therapeutic Drug Monitoring

Samples to determine trough concentration should be procured just prior to the third dose, often 0.5 hours . ASSUMPTION: STEADYSTATE IS ACHIEVED. Generally, serum samples should be obtained at steady-state when all of the pharmacokinetic values are at equilibrium. Monitoring trough concentrations alone is acceptable in otherwise normal healthy patients, following an initial set of peak and trough concentrations. For patients with fluctuating renal function, a pre-dose serum concentration and a series of post-dose serum concentrations should be obtained during the course of therapy.

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Gentamicin
Therapeutic Indications
Infections caused by gram-negative aerobes (Klebsiella, E.coli, Enterococci, Pseudomonas and Serratia. Urinary tract, bone/joint, soft tissue (including burns), endocarditis, and intra-abdominal/pelvic infections. Empiric regimens for febrile neutropenic patients.

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Gentamicin Toxicity and Adverse Effects

Ototoxicity Characterized by cochlear damage with loss of high frequency tone. Vestibular toxicity may be more clinically obvious with nystagmus and ataxia. Excess peak concentrations may be related to the development of ototoxicity. Nephrotoxicity Evidence suggests that the risk increases with increasing serum concentrations. Unclear whether nephrotoxicity is due to underlying pathology, concurrent therapy with other nephrotoxic agents, or to the antibiotic. Other Hypersensitivity reactions, and neuromuscular blockade
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Gentamicin Therapeutic Drug Monitoring

Desired peak serum concentrations = 6.0 - 10 mg/L Desired trough serum concentrations = 0.5 2.0 mg/L

! Due to large interpatient variability in the pharmacokinetics and potential ototoxicity and nephrotoxicity, serum concentrations should be monitored, especially in high-risk patients, those with renal impairment or who are given other ototoxic and/or nephrotoxic agents concurrently.

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Gentamicin Therapeutic Drug Monitoring

Monitoring serum concentrations has been a challenge to clinicians due to the distributional characteristics of the drug. ASSUMPTION: FIRST-ORDER

ELIMINATION FROM ONE-COMPARTMENT.

The peak concentration is drawn 30 minutes following the 30-minute intermittent intravenous infusion. ASSUMPTION: DISTRIBUTION IS COMPLETE WITH THIS SAMPLING STRATEGY.

Samples to determine trough concentration should be procured just prior to the third dose, often 0.5 hours . ASSUMPTION: STEADY-STATE ACHIEVED. Monitoring trough concentrations alone is acceptable in otherwise normal healthy patients, following an initial set of peak and trough concentrations. For patients with fluctuating renal function, a pre-dose serum concentration and a series of post-dose serum concentrations should be obtained during the course of therapy.
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Pharmacokinetics of Gentamicin and Vancomycin

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Sample Vancomycin Pharmacokinetic Calculations

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Vancomycin Pharmacokinetic Profile of Sample Patient

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Calculations
(1) Slope (Elimination Rate Constant, kel) Cp1 at 2.08 hours (60+65 min) = 27 mg/L Cp2 at 17.33 hours (18 hrs-40min) = 1 mg/L
ke = ln (Cp1/Cp2) = t2-t1 ln (27/1) = 0.22 h-1 17.33 2.08

(2) Half-life (t1/2)

t1/2 = 0.693 = ke 0.693 0.22 h-1 = 3.15 h-1

(3) Apparent Volume of Distribution (Vd)

Vd = Dose = Cp1 - Cp2 35 mg 27 1 mg/L = 1.35 L

(4) New Dose

Desire a peak = 30 mg/L (35 mg/27 mg/L) = (x/30 mg/L) x = 38.89 mg; 40 mg

(5) New Dosage Interval

Desire a trough = 6 mg/L ln (target peak/target trough) = ln (31/6) = 7.5 hours Q8H
ke 0.22 h-1
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Comparison of Pharmacokinetic Methods

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Gentamicin Sample Pharmacokinetic Calculations

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Gentamicin Pharmacokinetic Profile of Sample Patient

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Calculations
(1) Slope (Elimination Rate Constant, kel) Cp1 at 1.33 hours (30+50 min) = 6.2 mg/L Cp2 at 18.2 hours = 1.7 mg/L (2) Half-life (t1/2) (3) Apparent Volume of Distribution (Vd) (4) New Dose (5) New Dosage Interval
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Comparison of Pharmacokinetic Methods

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Pharmacokinetic Equations

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Pharmacokinetic Equations

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Pharmacokinetic Equations

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Pharmacokinetic Equations

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Pharmacokinetic Equations

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Dosing in Renal Insufficiency

A linear relationship between Clvanc and CLcr

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Dosing in Renal Insufficiency

A linear relationship between Clvanc and CLcr

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Dosing in Renal Insufficiency

A linear relationship between Clvanc and CLcr

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